Benzimidazoles with antithrombotic activity

ABSTRACT

Novel benzimidazoles having antithrombotic activity. Exemplary are:(a) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,(b) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole, and(c) (R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole.

RELATED APPLICATIONS

This is a continuation of Ser. No. 09/735,159, filed Dec. 12, 2000, nowU.S. Pat. No. 6,451,832 which claims the benefit of a U.S. ProvisionalApplication 60/175,163 filed Jan. 7, 2000.

FIELD OF THE INVENTION

The present invention relates to novel benzimidazoles, methods formaking them, pharmaceutical compositions comprising them, and their useas, inter alia, antithrombotic agents.

DESCRIPTION OF THE INVENTION

The present invention relates to benzimidazoles of general formula

the tautomers, the stereoisomers, the mixtures thereof, the prodrugs,the derivatives thereof which contain a group which is negativelycharged under physiological conditions instead of a carboxy group, andthe salts thereof, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases which have valuableproperties.

The compounds of the above general formula I wherein R_(a) denotes astraight-chained C₁₋₃-alkyl group which is substituted in the 1 positionby a pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl group optionallysubstituted by a C₁₋₃-alkyl group and by an amino group monosubstitutedby a cyano-C₁₋₄-alkyl group, and/or R_(c) denotes a cyano group or a1,2,4-oxadiazol-3-yl group substituted in the 5 position by a C₁₋₃-alkylor phenyl group, while the phenyl substituent may be substituted by afluorine, chlorine or bromine atom or by a C₁₋₃-alkyl group, arevaluable intermediate products for preparing the other compounds ofgeneral formula I, and the compounds of the above general formula Iwherein R_(c) denotes one of the following amidino groups, and thetautomers, stereoisomers, mixtures thereof, the prodrugs, thederivatives thereof which contain a group which is negatively chargedunder physiological conditions instead of a carboxy group, and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic salts, and the stereoisomers thereof, have valuablepharmacological properties, particularly an antithrombotic activity.

In the above general formula

R_(a) denotes a straight-chained C₁₋₃-alkyl group wherein the hydrogenatoms may be wholly or partially replaced by fluorine atoms and which issubstituted in the 1 position

by a pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl group optionallysubstituted by a C₁₋₃-alkyl group and

by an amino group which is monosubstituted by a carboxy-C₁₋₄-alkyl,cyano-C₁₋₄alkyl or tetrazolyl-C₁₋₄-alkyl group,

or by a C₁₋₃-alkyl group which is terminally substituted by anN-(carboxy-C₁₋₃-alkylaminocarbonyl)-amino group optionally substitutedby a C₁₋₃-alkyl group at one or both amino nitrogen atoms, by acarboxy-C₁₋₃-alkoxy, N-(carboxy-C₁₋₃-alkyl)-amino,N-(C₁₋₃alkyl)-N-(carboxy-C₁₋₃alkyl)-amino,N-(carboxy-C₁₋₃alkylsulphonyl)-amino,N-(C₁₋₃alkyl)-N-(carboxy-C₁₋₃alkylsulphonyl)-amino ortetrazolyl-C₁₋₃-alkyl group,

R_(b) denotes a C₁₋₃-alkyl group and

R_(c) denotes an amidino group, a cyano group or a 1,2,4-oxadiazol-3-ylgroup substituted in the 5 position by a C₁₋₃-alkyl or phenyl group,while the phenyl substituent may be substituted by a fluorine, chlorineor bromine atom or by a C₁₋₃-alkyl group.

The carboxy groups, mentioned in the above definition of the groups, mayalso be replaced by a group which can be converted in vivo into acarboxy group or by a group which is negatively charged underphysiological conditions or

the amino and imino groups mentioned in the above definition of thegroups may also be substituted by a group which can be cleaved in vivo.Such groups are described, for example, in WO 98/46576 and by N. M.Nielson et al. in International Journal of Pharmaceutics 39, 75-85(1987).

By a group which can be converted in vivo into a carboxy group is meantfor example a hydroxmethyl group, a carboxy group esterified with analcohol wherein the alcoholic moiety is preferably a C₁₋₆-alkanol, aphenyl-C₁₋₃-alkanol, a C₃₋₉-cycloalkanol, whilst a C₅₋₈-cycloalkanol mayadditionally be substituted by one or two C₁₋₃-alkyl groups, aC₅₋₈-cycloalkanol, wherein a methylene group in the 3 or 4 position isreplaced by an oxygen atom or by an imino group optionally substitutedby a C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkoxycarbonyl orC₂₋₆-alkanoyl group and the cycloalkanol moiety may additionally besubstituted by one or two C₁₋₃-alkyl groups, a C₄₋₇-cycloalkenol, aC₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, a C₃₋₅-alkinol orphenyl-C₃₋₅-alkinol, with the proviso that no bond to the oxygen atomstarts from a carbon atom which carries a double or triple bond, aC₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol having a total of 8 to 10carbon atoms which may additionally be substituted in the bicycloalkylmoiety by one or two C₁₋₃-alkyl groups, a1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula

R_(d)—CO—O—(R_(e)CR_(f))—OH,

wherein

R_(d) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or phenyl-C₁₋₃-alkylgroup,

R_(e) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or phenylgroup and

R_(f) denotes a hydrogen atom or a C₁₋₃-alkyl group,

by a group which is negatively charged under physiological conditions ismeant a group such as a tetrazol-5-yl, phenylcarbonylaminocarbonyl,trifluoromethylcarbonylaminocarbonyl, C₁₋₆-alkylsulphonylamino,phenylsulphonylamino, benzylsulphonylamino,trifluoromethylsulphonylamino, C₁₋₆-alkylsulphonylaminocarbonyl,phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl orperfluoro-C₁₋₆-alkylsulphonylaminocarbonyl group

and by a group which can be cleaved in vivo from an imino or amino groupis meant, for example, a hydroxy group, an acyl group such as a benzoylgroup optionally mono- or disubstituted by fluorine, chlorine, bromineor iodine atoms or by C₁₋₃-alkyl or C₁₋₃-alkoxy groups, whilst thesubstituents may be identical or different, a pyridinoyl group or aC₁₋₁₆-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl,pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl orallyloxycarbonyl group, a C₁₋₁₆-alkoxycarbonyl or C₁₋₁₆-alkylcarbonyloxygroup wherein hydrogen atoms may be wholly or partially replaced byfluorine or chlorine atoms, such as the methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl,nonyloxycarbonyl, decyloxycarbonyl,

undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl,methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy,propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy,tert.butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy,octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy,undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, aphenyl-C₁₋₆-alkoxycarbonyl group such as the benzyloxycarbonyl,phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionylgroup wherein the amino group may be mono- or disubstituted byC₁₋₆-alkyl or C₃₋₇-cycloalkyl groups and the substituents may beidentical or different, a C₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl,R_(d)—CO—O—(R_(d)CR_(f))—O—CO, C₁₋₆-alkyl-CO—NH—(R_(g)CR_(h))—O—CO orC₁₋₆alkyl-CO—O—(R_(g)CR_(h))—(R_(g)CR_(h))—O—CO group wherein R_(d) toR_(f) are as hereinbefore defined,

R_(g) and R_(h), which may be identical or different, denote hydrogenatoms or C₁₋₃-alkyl groups.

Furthermore, the saturated alkyl and alkoxy moieties which contain morethan 2 carbon atoms mentioned in the above definitions also include thebranched isomers thereof such as the isopropyl, tert.butyl, isobutylgroup, etc., for example.

Preferred compounds of general formula I mentioned above are thosewherein

R_(b) and R_(c) are as hereinbefore defined and

R_(a) is as hereinbefore defined, with the proviso that one substituentdenotes an unbranched C₁₋₃-alkyl group or a 2,5-dihydropyrrolocarbonylgroup optionally substituted by a C₁₋₃-alkyl group,

or R_(a) denotes an ethyl group which is substituted in the 1 position

by a pyrrolidinocarbonyl group and

by an amino group, while the amino group is substituted by anethoxycarbonylmethyl group which is substituted in the ethoxy moiety inthe 2 position by a methoxy, dimethylamino or tolyl group, by acarboxymethyl, C₃₋₄-alkoxycarbonylmethyl, cyclohexyloxycarbonylmethyl,3-(C₂₋₃-alkoxycarbonyl)-propyl or tetrazolylmethyl group,

R_(b) denotes a methyl group and

R_(c) denotes an amidino group substituted by a benzoyl, methylbenzoyl,fluorobenzoyl group or trifluoromethylbenzoyl group or

R_(a) denotes an ethyl group which is substituted in the 1 position

by a pyrrolidinocarbonyl group substituted in the 2 position by a methylgroup and

by an amino group, whilst the amino group is substituted by acarboxymethyl or ethoxycarbonylmethyl group,

R_(b) denotes a methyl group and

R_(c) denotes an amidino group or

R_(a) denotes an ethyl group which is substituted in the 1 position

by a pyrrolidinocarbonyl group and

by an amino group substituted by a carboxymethyl,C₃₋₄-alkoxycarbonylmethyl or tetrazolylmethyl group or

by a methyl group, whilst the methyl group is substituted by atetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy,ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methyl amino,N-[2-(C₁₋₃-alkoxycarbonyl)-ethyl]-N-methylamino,N-(carboxymethylaminocarbonyl)-N-methyl-amino,N—(C₁₋₃alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino,N-(carboxymethylsulphonyl)-N-methyl-amino orN—(C₁₋₃alkoxycarbonylmethylsulphonyl)-N-methyl-amino group,

R_(b) denotes a methyl group and

R_(c) denotes an amidino group,

the tautomers, the isomers and the salts thereof.

Particularly preferred compounds of the above general formula I are theabove-mentioned compounds of general formula I with the exception of

(1)2-[4-(N-phenylcarbonyl-amidino)-phenylaminomethyl]-1-methyl-5-[1-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand

(2)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,

the tautomers, the isomers and the salts thereof.

Most particularly preferred compounds of the above general formula I arethose wherein

R_(a) denotes an ethyl group which is substituted in the 1 position

by a 2,5-dihydropyrrolocarbonyl group optionally substituted by a methylgroup and

by an amino group which may be substituted by aC₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl group wherein the C₂₋₄-alkoxy moiety isterminally monosubstituted by a methoxy, dimethylamino, phenyl or tolylgroup, by a carboxy-C₁₋₄-alkyl, cyclohexyloxycarbonyl-C₁₋₄-alkyl ortetrazolyl-C₁₋₄-alkyl group, or

by a C₁₋₃-alkyl group which is terminally substituted by anN-(carboxy-C₁₋₃-alkylaminocarbonyl)-amino orN—(C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylaminocarbonyl)-amino group optionallysubstituted at one or both amino nitrogen atoms by a C₁₋₃-alkyl group,by a carboxy-C₁₋₃-alkoxy, C₁₋₃-alkoxycarbonyl-C₁₋₃-alkoxy,N—(C₁₋₃-alkyl)-N-(carboxy-C₁₋₃alkyl)-amino,N—(C₁₋₃-alkyl)-N—(C₁₋₃alkoxycarbonyl-C₁₋₃alkyl)-amino,N—(C₁₋₃alkyl)-N-(carboxy-C₁₋₃-alkylsulphonyl)-amino orN—(C₁₋₃-alkyl)-N—(C₁₋₃alkoxycarbonyl-C₁₋₃alkylsulphonyl)-amino ortetrazolyl-C₁₋₃alkyl group,

R_(b) denotes a methyl group and

R_(c) denotes an amidino group optionally substituted by a benzoyl,methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group

or R_(a) denotes an ethyl group which is substituted in the 1 position

by a pyrrolidinocarbonyl group and

by an amino group, whilst the amino group is substituted by anethoxycarbonylmethyl group which is substituted in the 2 position by amethoxy, dimethylamino or tolyl group, by a carboxymethyl,propyloxycarbonylmethyl, isopropyloxycarbonylmethyl,isobutyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl,3-(C₂₋₃-alkoxycarbonyl)-propyl or tetrazolylmethyl group,

R_(b) denotes a methyl group and

R_(c) denotes an amidino group substituted by a benzoyl, methylbenzoyl,fluorobenzoyl group or trifluoromethylbenzoyl group or

R_(a) denotes an ethyl group which is substituted in the 1 position

by a pyrrolidinocarbonyl group substituted in the 2 position by a methylgroup and

by an amino group, whilst the amino group is substituted by acarboxymethyl or ethoxycarbonylmethyl group,

R_(b) denotes a methyl group and

R_(c) denotes an amidino group or

R_(a) denotes an ethyl group which is substituted in the 1 position

by a pyrrolidinocarbonyl group and

by an amino group substituted by a carboxymethyl orC₃₋₄-alkoxycarbonylmethyl group or

by a methyl group, whilst the methyl group is substituted by atetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy,ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methyl-amino,N-[2-(C₁₋₃-alkoxycarbonyl)-ethyl]-N-methyl-amino,N-(carboxymethylaminocarbonyl)-N-methyl-amino,N—(C₁₋₃-alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino,N-(carboxymethylsulphonyl)-N-methyl-amino orN—(C₁₋₃alkoxycarbonylmethylsulphonyl)-N-methyl-amino group,

R_(b) denotes a methyl group and

R_(c) denotes an amidino group,

the tautomers, the isomers and the salts thereof.

The following may be mentioned as examples of particularly preferredcompounds:

(1)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,

(2)2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,

(3)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,

(4)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,

(5)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-[(R,S)-1-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole,

(6)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazoleand

(7)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(cyclohexyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,

the isomers and the salts thereof.

According to the invention, the compounds of general formula I areobtained by methods known per se, for example by the following methods:

a) In order to prepare a compound of general formula I wherein R_(c)denotes a cyano group or a 1,2,4-oxadiazol-3-yl group substituted in the5 position by a C₁₋₃-alkyl or phenyl group, while the phenyl substituentmay be substituted by a fluorine, chlorine or bromine atom or by aC₁₋₃-alkyl group:

cyclising a compound of general formula

 optionally formed in the reaction mixture

wherein

R_(a) and R_(b) are as hereinbefore defined,

R_(c)′ denotes a cyano group or a 1,2,4-oxadiazol-3-yl group substitutedin the 5 position by a C₁₋₃-alkyl or phenyl group, while the phenylsubstituent may be substituted by a fluorine, chlorine or bromine atomor by a C₁₋₃-alkyl group,

Z₁ and Z₂, which may be identical or different, denote amino, hydroxy ormercapto groups optionally substituted by alkyl groups with 1 to 6carbon atoms or

Z₁ and Z₂ together denote an oxygen or sulphur atom, an imino groupoptionally substituted by an alkyl group with 1 to 3 carbon atoms, analkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms.

The cyclisation is conveniently carried out in a solvent or mixture ofsolvents such as ethanol, isopropanol, glacial acetic acid, benzene,chlorobenzene, toluene, xylene, glycol, glycolmonomethylether,diethyleneglycoldimethylether, sulpholane, dimethylformamide ortetraline or in an excess of the acylating agent used to prepare thecompound of general formula II, e.g. in the corresponding nitrile,anhydride, acid halide, ester or amide, for example at temperaturesbetween 0 and 250° C., but preferably at the boiling temperature of thereaction mixture, optionally in the presence of a condensing agent suchas phosphorus oxychloride, thionyl chloride, sulphuryl chloride,sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid,hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid,acetic anhydride, N,N-dicyclohexyl-carbodiimide or optionally also inthe presence of a base such as potassium ethoxide or potassiumtert.butoxide. The cyclisation may, however, also be carried out withouta solvent and/or condensing agent.

b) In order to prepare a compound of general formula I wherein R_(c)denotes an amidino group:

reacting a compound of general formula

 optionally formed in the reaction mixture

wherein

R_(a) and R_(b) are as hereinbefore defined and

Z₄ denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy,n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthiogroup such as the methylthio, ethylthio, n-propylthio or benzylthiogroup,

with ammonia or with the salts thereof.

The reaction is conveniently carried out in a solvent such as methanol,ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between0 and 150° C., preferably at temperatures between 0 and 80° C., withammonia or one of its salts such as for example ammonium carbonate orammonium acetate.

A compound of general formula III is obtained for example by reacting acorresponding cyano compound with a corresponding alcohol such asmethanol, ethanol, n-propanol, isopropanol or benzylalcohol in thepresence of an acid such as hydrochloric acid or by reacting acorresponding amide with a trialkyloxonium salt such astriethyloxonium-tetra-fluoroborate in a solvent such as methylenechloride, tetrahydrofuran or dioxane at temperatures between 0 and 50°C., but preferably at 20° C., or a corresponding nitrile with hydrogensulphide, conveniently in a solvent such as pyridine ordimethylformamide and in the presence of a base such as triethylamineand subsequent alkylation of the thioamide formed with a correspondingalkyl or aralkyl halide.

c) In order to prepare a compound of general formula I wherein R_(a)contains a carboxy group and R_(c) is as hereinbefore defined:

Converting a compound of general formula

wherein

R_(b) and R_(c) are as hereinbefore defined and

R_(a)′ has the meanings given hereinbefore for R_(a), with the provisothat R_(a) contains a group which can be converted into a carboxy groupby hydrolysis, treatment with an acid or base, thermolysis orhydrogenolysis,

by hydrolysis, treatment with an acid or base, thermolysis orhydrogenolysis into a compound of general formula I wherein R_(a)contains a carboxy group.

A group which may be converted into a carboxy group may be, for example,a carboxyl group protected by a protecting group such as the functionalderivatives thereof, e.g. the unsubstituted or substituted amides,esters, thioesters, trimethylsilylesters, orthoesters or iminoestersthereof, which are conveniently converted into a carboxyl group byhydrolysis,

the esters thereof with tertiary alcohols, e.g. the tert.butyl ester,which are conveniently converted into a carboxyl group by treatment withan acid or thermolysis, and

the esters thereof with aralkanols, e.g. the benzyl ester, which areconveniently converted into a carboxyl group by hydrogenolysis.

The hydrolysis is conveniently carried out either in the presence of anacid such as hydrochloric acid, sulphuric acid, phosphoric acid, aceticacid, trichloroacetic acid, trifluoroacetic acid or the mixtures thereofor in the presence of a base such as lithium hydroxide, sodium hydroxideor potassium hydroxide in a suitable solvent such as water,water/methanol, water/ethanol, water/isopropanol, methanol, ethanol,water/tetrahydrofuran or water/dioxane at temperatures between −10 and120° C., e.g. at temperatures between room temperature and the boilingtemperature of the reaction mixture.

If a compound of formula IV for example contains the tert.butyl ortert.butyloxycarbonyl group, this may also be cleaved by treatment withan acid such as trifluoroacetic acid, formic acid, p-toluenesulphonicacid, sulphuric acid, hydrochloric acid, phosphoric acid orpolyphosphoric acid optionally in an inert solvent such as methylenechloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran ordioxane, preferably at temperatures between −10 and 120° C., e.g. attemperatures between 0 and 60° C., or also thermally, optionally in aninert solvent such as methylene chloride, chloroform, benzene, toluene,tetrahydrofuran or dioxane and preferably in the presence of a catalyticamount of an acid such as p-toluenesulphonic acid, sulphuric acid,phosphoric acid or polyphosphoric acid, preferably at the boilingtemperature of the solvent used, e.g. at temperatures between 40 and120° C.

If a compound of formula IV contains the benzyloxy or benzyloxycarbonylgroup, for example, this may also be cleaved hydrogenolytically in thepresence of a hydrogenation catalyst such as palladium/charcoal in asuitable solvent such as methanol, ethanol, ethanol/water, glacialacetic acid, ethyl acetate, dioxane or dimethylformamide, preferably attemperatures between 0 and 50° C., e.g. at room temperature, and at ahydrogen pressure of 1 to 5 bar.

d) In order to prepare a compound of general formula I wherein R_(c)denotes an amidino group which is substituted by a group which can becleaved in vivo:

reacting a compound of general formula

wherein

R_(a) and R_(b) are as hereinbefore defined, with a compound of generalformula

Z₅—R₉  (VII),

wherein

R₉ denotes the acyl group of one of the abovementioned groups which canbe cleaved in vivo and

Z₅ denotes a nucleofugic leaving group such as a halogen atom, e.g. achlorine, bromine or iodine atom, or a p-nitrophenyl group.

The reaction is preferably carried out in a solvent such as methanol,ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane,dimethylsulphoxide or dimethylformamide optionally in the presence of aninorganic or a tertiary organic base, preferably at temperatures between20° C. and the boiling temperature of the solvent used.

With a compound of general formula VII wherein Z₅ denotes a nucleofugicleaving group, the reaction is preferably carried out in a solvent suchas methylene chloride, acetonitrile, tetrahydrofuran, toluene,acetone/water, dimethylformamide or dimethylsulphoxide, optionally inthe presence of a base such as sodium hydride, potassium carbonate,potassium tert.butoxide or N-ethyl-diisopropylamine at temperaturesbetween 0 and 60° C.

e) In order to prepare a compound of general formula I wherein R_(c)denotes one of the abovementioned amidino groups:

catalytic hydrogenation of a compound of general formula

wherein

R_(a) and R_(b) are as hereinbefore defined and

R_(c)″ denotes a 1,2,4-oxadiazol-3-yl group substituted in the 5position by a C₁₋₃-alkyl or phenyl group, wherein the phenyl substituentmay be substituted by a fluorine, chlorine or bromine atom or by aC₁₋₃-alkyl group, and if necessary subsequent hydrolysis of a compoundthus obtained.

The catalytic hydrogenation is preferably carried out in a suitablesolvent such as methanol, ethanol, ethanol/water, glacial acetic acid,ethanol/glacial acetic acid, ethyl acetate, dioxane or dimethylformamidein the presence of a hydrogenation catalyst such as palladium/charcoal,preferably at temperatures between 0 and 50° C., e.g. at roomtemperature, and at a hydrogen pressure of 1 to 5 bar.

The hydrolysis which may follow is conveniently carried out either inthe presence of an acid such as hydrochloric acid, sulphuric acid,phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acidor mixtures thereof or in the presence of a base such as lithiumhydroxide, sodium hydroxide or potassium hydroxide in a suitable solventsuch as water, water/methanol, water/ethanol, water/isopropanol,methanol, ethanol, water/tetrahydrofuran or water/dioxane attemperatures between −10 and 120° C., e.g. at temperatures between roomtemperature and the boiling temperature of the reaction mixture.

f) In order to prepare a compound of general formula I wherein R_(a)denotes an amino-C₁₋₃-alkyl group in which the amino group ismonosubstituted by a carboxy-C₁₋₄-alkyl or tetrazolyl-C₁₋₃alkyl group:

alkylating a compound of general formula

wherein

R_(b) and R_(c) are as hereinbefore defined and

R_(a)″ denotes an amino-C₁₋₃-alkyl group, with a compound of generalformula

R_(a)′″—Z₇  (X)

wherein

R_(a)′″ denotes a carboxy-C₁₋₄-alkyl or tetrazolyl-C₁₋₄-alkyl group and

Z₇ denotes a nucleofugic leaving group such as a halogen atom or asulphonic acid ester group, e.g. a chlorine, bromine or iodine atom, ora p-nitrophenyl group.

The alkylation is conveniently carried out in a solvent such asmethylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide,dimethylformamide or acetone, optionally in the presence of a reactionaccelerator such as sodium or potassium iodide and preferably in thepresence of a base such as sodium carbonate or potassium carbonate or inthe presence of a tertiary organic base such as N-ethyl-diisopropylamineor N-methyl-morpholine, which may simultaneously also act as solvent, oroptionally in the presence of silver carbonate or silver oxide attemperatures between −30 and 100° C., but preferably at temperaturesbetween −10 and 80° C.

If according to the invention a compound of general formula I isobtained wherein R_(a) contains a carboxy group, this may subsequentlybe converted by esterification into a corresponding compound whereinR_(a) contains an esterified carboxy group, and/or

if a compound of general formula I is obtained wherein R_(a) contains anesterified carboxy group, this may subsequently be converted bytransesterification into a corresponding compound wherein R_(a) containsanother esterified carboxy group, and/or

if a compound of general formula I is obtained wherein R_(a) contains acyano group, this may subsequently be converted into a correspondingcompound wherein R_(a) contains a tetrazolyl group.

The subsequent esterification is carried out with a correspondingalcohol, usefully in a solvent or mixture of solvents such as methylenechloride, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane, but preferably in an excess of thealcohol used, optionally in the presence of an acid such as hydrochloricacid or in the presence of a dehydrating agent, e.g. in the presence ofisobutyl chloroformate, thionyl chloride, trimethylchlorosilane,hydrochloric acid, sulphuric acid, methanesulphonic acid,p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexyl carbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N′-carbonyldiimidazole orN,N′-thionyldiimidazole, triphenylphosphine/carbon tetrachloride ortriphenylphosphine/diethyl azodicarboxylate, optionally in the presenceof a base such as potassium carbonate, N-ethyl-diisopropylamine orN,N-dimethylamino-pyridine, conveniently at temperatures between 0 and150° C., preferably at temperatures between 0 and 80° C., or with acorresponding halide in a solvent such as methylene chloride,tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide oracetone, optionally in the presence of a reaction accelerator such assodium or potassium iodide and preferably in the presence of a base suchas sodium carbonate or potassium carbonate or in the presence of atertiary organic base such as N-ethyl-diisopropylamine orN-methyl-morpholine, which may also serve as solvent at the same time,or optionally in the presence of silver carbonate or silver oxide attemperatures between −30 and 100° C., but preferably at temperaturesbetween −10 and 80° C.

The subsequent transesterification is carried out with a correspondingalcohol, conveniently in a solvent or mixture of solvents such asmethylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane, but preferably in an excess of thealcohol used, conveniently in the presence of an acid such ashydrochloric acid or in the presence of a compound such as2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane attemperatures between 0 and 150° C., preferably at temperatures between 0and 80° C.

The subsequent conversion of a cyano group into a tetrazolyl group ispreferably carried out in a solvent such as benzene, toluene ordimethylformamide at temperatures between 80 and 150° C., preferably at120 and 130° C. The hydrazoic acid needed is conveniently liberatedduring the reaction from an alkali metal azide, e.g. from sodium azide,in the presence of a weak acid such as ammonium chloride. The reactionmay also take place with another salt or derivative of hydrazoic acid,preferably with aluminium azide or tributyl tin azide, the tetrazolecompound optionally obtained in this way being liberated from the saltcontained in the reaction mixture by acidification with a dilute acidsuch as 2N hydrochloric acid or 2N sulphuric acid.

In the reactions described hereinbefore, any reactive groups presentsuch as carboxy, amino or alkylamino groups may be protected during thereaction by conventional protecting groups which are cleaved again afterthe reaction.

For example, a protecting group for a carboxy group may be atrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup and

protecting groups for an amino or alkylamino group may be an acetyl,trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groupand additionally, for the amino group, a phthalyl group.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,acetic acid/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such aslithium hydroxide, sodium hydroxide or potassium hydroxide or by ethercleavage, e.g. in the presence of iodotrimethylsilane, at temperaturesbetween 0 and 100° C., preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleavedhydrogenolytically, for example, with hydrogen in the presence of acatalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 50° C., but preferablyat room temperature, and at a hydrogen pressure of 1 to 7 bar, butpreferably 3 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of an oxidantsuch as cerium(IV)ammonium nitrate in a solvent such as methylenechloride, acetonitrile or acetonitrile/water at temperatures between 0and 50° C., but preferably at room temperature.

A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisol.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20 and 50° C.

An allyloxycarbonyl group is cleaved by treating with a catalytic amountof tetrakis-(triphenylphosphine)-palladium(O), preferably in a solventsuch as tetrahydrofuran and preferably in the presence of an excess of abase such as morpholine or 1,3-dimedone at temperatures between 0 and100° C., preferably at room temperature and under inert gas, or bytreating with a catalytic amount oftris-(triphenylphosphine)-rhodium(I)chloride in a solvent such asaqueous ethanol and optionally in the presence of a base such as1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70° C.

The compounds of general formulae II to X used as starting materials,some of which are known from the literature, are obtained by methodsknown from the literature, and moreover their preparation is describedin the Examples.

The chemistry of the compounds of general formula II is described forexample by Jack Robinson in J. Chem. Soc. 1941, 744, that of thebenzimidazoles is described by Katritzky and Rees in ComprehensiveHeterocyclic Chemistry, Oxford, Pergamon Press, 1984, by Schaumann inHetarene III, Methoden der organischen Chemie (Houben-Weyl), 4thedition, published by Thieme, Stuttgart 1993.

Thus, for example, a compound of general formula II is obtained byacylating a corresponding o-diamino compound with a correspondingreactive acyl derivative,

a compound of general formulae III, IV, VI, VIII and IX is obtained bycyclising a corresponding, substituted compound according to process a)and if necessary subsequently converting a cyano compound thus obtainedinto the desired starting compound using known methods.

Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained whichoccur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes and compounds ofgeneral formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiralphases or by recrystallisation from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a(+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I may be converted into the saltsthereof, particularly for pharmaceutical use into the physiologicallyacceptable salts with inorganic or organic acids. Acids which may beused for this purpose include for example hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, if the new compounds of formula I contain a carboxy group,they may subsequently, if desired, be converted into the salts thereofwith inorganic or organic bases, particularly for pharmaceutical useinto the physiologically acceptable salts thereof.

Suitable bases for this purpose include for example sodium hydroxide,potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

As already mentioned, the new compounds of general formula I and thesalts thereof have valuable properties. Thus, the compounds of generalformula I wherein R_(c) denotes a cyano group are valuable intermediateproducts for preparing the other compounds of general formula I, and thecompounds of general formula I wherein R_(c) denotes one of the amidinogroups mentioned hereinbefore, and the tautomers, the stereoisomers andthe physiologically acceptable salts thereof have valuablepharmacological properties, particularly an antithrombotic effect whichis preferably based on influencing thrombin or factor Xa, e.g. on aninhibitory effect on thrombin or factor Xa, on an effect of prolongingthe aPTT time and an inhibitory effect on related serine proteases suchas e.g. trypsin, urokinase factor VIIa, factor IX, factor XI and factorXII.

For example, the following compounds:

A=2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride,

B=(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochlorideand

C=(2)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride

were investigated as follows for their effects on prolonging the aPTTtime:

Materials Plasma, from Human Citrated Blood

PTT reagent, Boehringer Mannheim (524298),

Calcium solution (0.025 mol/l), Behring Werke, Marburg (ORH 056/57),

Diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61),

Biomatic B10 coagulometer, Desaga, Wiesloch.

Method

The aPTT time was determined using a Biomatic B10 coagulometer made byMessrs. Desaga.

The test substance was placed in the test tubes prescribed by themanufacturer together with 0.1 ml of human citrated plasma and 0.1 ml ofPTT reagent. The mixture was incubated for three minutes at 37° C. Theclotting reaction was started by the addition of 0.1 ml of calciumsolution. The time is measured using the apparatus from the addition ofthe calcium solution up to the clotting of the mixture. Mixtures towhich 0.1 ml of DBA buffer were added were used as the controls.

According to the definition, a dosage-activity curve was used todetermine the effective concentration of the substance, i.e. theconcentration at which the aPTT time is doubled compared with thecontrol.

The Table which follows contains the results found:

aPTT time Substance (ED₂₀₀ in μM) A 0.13 B 0.12 C 0.22

The compounds prepared according to the invention are well toleratedsince no toxic side effects could be detected at therapeutic doses;moreover, the corresponding prodrugs, for example the compounds ofExamples 1(6), 2, 3(2) and 3(5), exhibit good oral resorption.

In view of their pharmacological properties the new compounds and thephysiologically acceptable salts thereof are suitable for the preventionand treatment of venous and arterial thrombotic diseases, such as forexample the treatment of deep leg vein thrombosis, for preventingreocclusions after bypass operations or angioplasty (PT(C)A), andocclusion in peripheral arterial diseases such as pulmonary embolism,disseminated intravascular coagulation, for preventing coronarythrombosis, stroke and the occlusion of shunts. In addition, thecompounds according to the invention are suitable for antithromboticsupport in thrombolytic treatment, such as for example with rt-PA orstreptokinase, for preventing long-term restenosis after PT(C)A, forpreventing metastasis and the growth of clot-dependent tumours andfibrin-dependent inflammatory processes, e.g. in the treatment ofpulmonary fibrosis.

The dosage required to achieve such an effect is appropriately 0.1 to 30mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 50mg/kg, preferably 0.3 to 30 mg/kg by oral route, in each caseadministered 1 to 4 times a day. For this purpose, the compounds offormula I prepared according to the invention may be formulated,optionally together with other active substances, with one or more inertconventional carriers and/or diluents, e.g. with corn starch, lactose,glucose, microcrystalline cellulose, magnesium stearate,polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,water/glycerol, water/sorbitol, water/polyethyleneglycol,propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fattysubstances such as hard fat or suitable mixtures thereof, to produceconventional galenic preparations such as plain or coated tablets,capsules, powders, suspensions or suppositories.

The Examples which follow are intended to illustrate the invention:

EXAMPLE 1(R)-2-[4-[N-(4-methyl-phenylcarbonyl)-amidino]-phenylamino-methyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

a. (R)-5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidin-2,4-dione

10.0 g (4.45 mmol) of(R)-5-(4-chlorophenyl)-5-methyl-imidazolidin-2,4-dione are addedbatchwise to 50 ml of fuming nitric acid at −25 to −35° C. After 45minutes at −25 to −20° C. the reaction mixture is poured onto ice water.The crystalline product is suction filtered, washed with water anddried.

Yield: 10.5 g (100% of theory), Melting point: 173-178° C. R_(f) value:0.30 (silica gel; cyclohexane/ethyl acetate=1:1)

b. (R)-2-amino-2-(4-chlor-3-nitro-phenyl)-propionic acid

10.5 g (0.044 mol) of(R)-5-(4-chloro-3-nitro-phenyl)-5-methyl-imidazolidine-2,4-dione arerefluxed in 200 ml of dioxane and 700 ml of 6N hydrochloric acid for 5days. The solution is concentrated by evaporation, the residue is takenup in water and extracted with ethyl acetate. The aqueous phase isconcentrated by evaporation, mixed with toluene and evaporated todryness. The residue is triturated with ether, suction filtered anddried.

Yield: 6.8 g (63% of theory), R_(f) value: 0.24 (Reversed phase RP8, 5%saline solution/methanol=1:1)

c.(R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionicacid

72.5 g (0.296 mol) of (R)-2-amino-2-(4-chloro-3-nitro-phenyl)-propionicacid are dissolved in 850 ml dioxane and 200 ml water and after theaddition of 108.7 ml (0.78 mol) of triethylamine and 136 g (0.623 mol)of di-tert.butyl dicarbonate stirred for 18 hours at room temperature.After the addition of 800 ml of 1N sodium hydroxide solution thesolution is stirred for 30 minutes and then extracted 3× with 500 ml ofether. The aqueous phase is adjusted to pH 7 with 1N hydrochloric acidand then to pH 4 with 5% citric acid. After extracting 4 times with 500ml of ethyl acetate, the combined organic phases are washed with water,dried, suction filtered through magnesium sulphate and concentrated byevaporation.

Yield: 86.8 g (85% of theory), R_(f) value: 0.3 (silica gel; methylenechloride/methanol=4:1+1% ammonia) C₁₄H₁₇ClN₂O₆ (344.7) Mass spectrum:(M−H)⁻=343

d.(R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3-nitro-phenyl)-propionicacid

96 g (0.278 mol) of(R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionicacid and 440 ml of methylamine solution (40% solution in water) areheated to 90° C. in a pressurised vessel for seven hours. After cooling,the reaction solution is adjusted to pH 3.5 by the addition of glacialacetic acid, whilst cooling with ice, and extracted with ethyl acetate.After the solvent has been evaporated off, the residue remaining iswashed with ether and dried.

Yield: 70 g (74% of theory), R_(f) value: 0.30 (silica gel; methylenechloride/ethanol=19:1+1% glacial acetic acid) C₁₅H₂₁N₃O₆ (339.3) Massspectrum: (M−H)⁻=338

e.(R)-2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonlamino-1-pyrrolidino-propanone

50 g (0.147 mol) of(R)-2-tert.butyloxycarbonylamino-2-(4-methylamino-3-nitro-phenyl)-propionicacid are dissolved in 275 ml of dimethylformamide and after the additionof 47.5 g (0.147 mol) ofO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate,24.5 g (0.334 mol) of pyrrolidine and 30 ml of (0.273 mol) ofN-methyl-morpholine the mixture is stirred for 20 hours at roomtemperature. The solution is poured onto ice water and acidified withcitric acid (pH 5-6). The precipitate formed is suction filtered, washedwith water and dried.

Yield: 45.5 g (79% of theory), R_(f) value: 0.6 (silica gel; petroleumether/ethyl acetate=1:1)

f.(R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone

25.5 g (65 mmol) of(R)-2-(4-methylamino-3-nitro-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanoneare dissolved in 650 ml of methanol and after the addition of 4.0 g ofpalladium on activated charcoal (20%) the mixture is hydrogenated for 2hours at room temperature. Then the catalyst is filtered off andconcentrated by evaporation.

Yield: 21.4 g (91% of theory), R_(f) value: 0.31 (silica gel; ethylacetate +1% ammonia)

g.(R)-2-[4-methylamino-3-(4-cyanophenylaminomethylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone

Prepared analogously to Example 1e from(R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate,4-cyano-phenylglycine and N-methyl-morpholine in dimethylformamide.

Yield: 100% of theory, R_(f) value: 0.47 (silica gel; ethyl acetate)

h.(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

47.7 g (0.042 mol) of(R)-2-[4-methylamino-3-(4-cyanophenylamino-methylcarbonylamino)-phenyl]-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanoneare refluxed in 300 ml of glacial acetic acid for 2 hours. The reactionmixture is added to ice water and adjusted to pH 8 with conc. ammonia.The precipitate formed is filtered off, washed with water and dried.

Yield: 46 g (100% of theory), R_(f) value: 0.3 (silica gel; ethylacetate +1% ammonia)

i.(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

25.1 g (50 mmol) of(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(N-tert.butyloxycarbonylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare dissolved in 500 ml of 6N hydrochloric acid at 35° C. and stirredfor one hour at this temperature. The solution is mixed with ice, madealkaline with ammonia and extracted with ethyl acetate. The combinedorganic extracts are dried and concentrated by evaporation.

Yield: 17.8 g (88% of theory), R_(f) value: 0.5 (silica gel; methylenechloride/ethanol=4:1+1% ammonia)

k.(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-(1-ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

4.2 g (10.44 mmol) of(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare dissolved in 100 ml of acetone and combined with 2.3 g (16.65 mmol)of potassium carbonate and 2.25 ml (20.2 mmol) of ethyl bromoacetate.The suspension is heated to 60° C. for 5 hours. After cooling thereaction mixture is stirred into 400 ml of ice water, the precipitateformed is filtered off, washed with water and dried. The crude productis chromatographed on silica gel, eluting with methylenechloride/ethanol (19:1 and 9:1). The uniform fractions are combined andconcentrated by evaporation.

Yield: 3.1 g (61% of theory), R_(f) value: 0.4 (silica gel; ethylacetate/ethanol=9:1)

l.(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1-ethoxycarbonylethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride

6.8 g (13.8 mmol) of(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare dissolved in 400 ml of saturated ethanolic hydrochloric acid andstirred for 23 hours at room temperature. The solvent is distilled off,the residue is dissolved in 200 ml of absolute ethanol and combined with20 g (0.21 mol) of ammonium carbonate. After 20 hours at roomtemperature 100 ml of ethanol are added and after another 10 hours'stirring at room temperature the mixture is filtered and evaporated todryness. The residue is stirred in 200 ml of acetone, filtered off,washed with ether and dried.

Yield: 7.6 g (100% of theory), R_(f) value: 0.61 (Reversed phase RP8; 5%sodium chloride solution/methanol=3:2) C₂₇H₃₆N₇O₃×HCl (505.64/542.09)Mass spectrum: (M+H)⁺=506

m.(R)-2-[4-[N-(4-methyl-phenylcarbonyl)-amidino]-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

A suspension of 0.7 g (1.2 mmol) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloridein 25 ml of methylene chloride is combined with 4.0 ml (28 mmol) oftriethylamine and 0.8 g (3.0 mmol) of 4-nitrophenyl 4-methyl-benzoateand heated to 50° C. for 3.5 hours, whereupon a clear solution isformed. After cooling, it is washed with sodium bicarbonate solution,saline solution and water, dried over magnesium sulphate andconcentrated by evaporation. The crude product is purified on silicagel, eluting with ethyl acetate/ethanol (50:1 and 9:1). The uniformfractions are combined, concentrated by evaporation, triturated withether, suction filtered and dried.

Yield: 0.5 g (66% of theory), R_(f) value: 0.50 (silica gel; ethylacetate/ethanol=9:1) C₃₅H₄₁N₇O₄ (623.75)

Mass spectrum: (M+H)⁺=624 (M+Na)⁺=646 (M−H)⁻=622

The following compounds are obtained analogously to Example 1:

(1)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate

Yield: 69% of theory, R_(f) value: 0.2 (silica gel; methylenechloride/ethanol=7:3+1% glacial acetic acid) C₂₈H₃₇N₇O₃×CH₃COOH(519.65/579.70) Mass spectrum: (M+H)⁺=520 (M−H)⁻=518

(2)(R)-2-[4-[N-(4-fluorophenylcarbonyl)amidino]-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 40% of theory, R_(f) value: 0.4 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₄H₃₈FN₇O₄ (627.72) Mass spectrum:(M+H)⁺=628 (M+Na)⁺=650 (M−H)⁻=626

(3)(R)-2-[4-[N-(4-trifluoromethyl-phenylcarbonyl)amidino]-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 47% of theory, R_(f) value: 0.53 (silica gel; methylenechloride/methanol/conc. ammonia=9:0.9:0.1) C₃₅H₃₈F₃N₇O₄ (677.73) Massspectrum: (M+H)⁺=678 (M+Na)⁺=700 (M−H)⁻=676

(4)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

(5)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride

Yield: 94% of theory, R_(f) value: 0.2 (Reversed phase RP8; 5% salinesolution/methanol=2:3) C₂₇H₃₃N₇O₃×2 HCl (503.6/576.51) Mass spectrum:(M+H)⁺=504 (M−H+HCl)⁻=538/540 (Cl)

(6)2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole

Yield: 71% of theory, R_(f) value: 0.3 (silica gel; ethylacetate/ethanol=9:1) C₃₄H₃₇N₇O₄ (607.72) Mass spectrum: (M+H)⁺=608(M+Na)⁺=630 (M−H)⁻=606

(7)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-[(R,S)-1-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochloride(mixture of diastereomers)

Yield: 88% of theory, R_(f) value: 0.3 (Reversed phase RP8; 5% salinesolution/methanol=3:2) C₂₈H₃₇N₇O₃×2 HCl (519.65/592.56) Mass spectrum:(M+H)⁺=520 (M+Cl)⁻=554/6 (Cl)

(8)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(3-ethoxycarbonyl-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 19% of theory, R_(f) value: 0.44 (silica gel; methylenechloride/methanol=4:1+1% glacial acetic acid) C₃₆H₄₃N₇O₄ (637.79) Massspectrum: (M+H)⁺=638 (M−H)⁻=636

(9)(R)-2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 70% of theory, R_(f) value: 0.37 (silica gel; ethylacetate/ethanol=9:1) C₃₅H₄₉N₇O₅ (647.82) Mass spectrum: (M+Na)⁺=670(M−H)⁻=646

EXAMPLE 2

(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

A solution of 0.3 g (0.53 mmol) of(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazolein 5 ml of n-butanol is mixed with 0.1 g (0.46 mmol) of2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane andstirred for 1 hour at room temperature. The reaction mixture is purifiedon silica gel, eluting with ethyl acetate/ethanol/conc. ammonia(50:0.95:0.05 and 20:0.95:0.05). The uniform fractions are combined andconcentrated by evaporation.

Yield: 0.19 g (57% of theory, R_(f) value: 0.45 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₆H₄₃N₇O₄ (637.78) Mass spectrum:(M+H)⁺=638 (M+Na)⁺=660 (M−H)⁻=636

The following compounds are obtained analogously to Example 2:

(1)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 16% of theory, R_(f) value: 0.48 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₆H₄₃N₇O₄ (637.78) Mass spectrum:(M+H)⁺=638 (M+Na)⁺=660 (M−H)⁻=636

(2)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-methoxy-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 43% of theory, R_(f) value: 0.31 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₅H₄₁N₇O₅ (639.76) Mass spectrum:(M+H)⁺=640 (M−H)⁻=638

(3)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-dimethylamino-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 23% of theory, R_(f) value: 0.26 (silica gel; methylenechloride/methanol/ammonia=9:0.9:0.1) C₃₆H₄₄N₈O₄ (652.8) Mass spectrum:(M+H)⁺=651 (M−H)⁻=653

(4)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-(2-methylphenyl)-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 23% of theory, R_(f) value: 0.52 (silica gel; ethylacetate/ethanol/ammonia=9:0.95:0.05) C₄₁H₄₅N₇O₄ (699.86) Mass spectrum:(M+H)⁺=700 (M+Na)⁺=722 (M−H)⁻=698

(5)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(cyclohexyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 34% of theory, R_(f) value: 0.49 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₈H₄₇N₇O₄ (663.83) Mass spectrum:(M+H)+664 (M+Na)⁺=686 (M−H)⁻=662

EXAMPLE 3

(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isopropyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole

2.1 ml of conc. sulphuric acid are added dropwise to a solution of 0.5 g(0.82 mmol) of(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazolein 12.3 ml of isopropanol. After 4 hours at 85° C. the solution iscooled and poured onto 250 ml of ice water. The pH is adjusted to 8.5 bythe addition of conc. ammonia. The precipitate formed is suctionfiltered, dried and purified on silica gel, eluting with methylenechloride +2% methanol +0.01% ammonia. The uniform fractions are combinedand concentrated by evaporation, the residue is triturated with ether,filtered off and dried.

Yield: 0.19 g (37% of theory), R_(f) value: 0.46 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₅H₃₉N₇O₄ (621.75) Mass spectrum:(M+H)⁺=622 (M+Na)⁺=644 (M−H)⁻=620

The following compounds are obtained analogously to Example 3:

(1)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole

Yield: 33% of theory, R_(f) value: 0.46 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₅H₃₉N₇O₄ (621.75) Mass spectrum:(M+H)⁺=622 (M+Na)⁺=644 (M−H)⁻=620

(2)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 36% of theory, R_(f) value: 0.45 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₅H₄₁N₇O₄ (623.76) Mass spectrum:(M+H)⁺=624 (M+Na)⁺=646 (M−H)⁻=622

(3)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-butyl-oxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride

Yield: 8% of theory, R_(f) value: 0.44 (silica gel; methylenechloride/methanol=4:1+1% ammonia) C₂₉H₃₉N₇O₃×2 HCl (533.69/606.6) Massspectrum: (M+H)⁺=534 (M−H)⁻=532

(4)(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-sulphate

Yield: 7% of theory, R_(f) value: 0.36 (silica gel; methylenechloride/methanol=4:1+1% ammonia) C₂₈H₃₇N₇O₃×H₂SO₄ (519.65/617.7) Massspectrum: (M+H)⁺=520

(5)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(cyclohexyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole

Yield: 22% of theory, R_(f) value: 0.60 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₃₈H₄₃N₇O₄ (661.81) Mass spectrum:(M+H)⁺=662 (M+Na)⁺=684 (M−H)⁻=660

(6)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(3-(isopropyloxycarbonyl)-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

(7)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(3-(n-propyloxycarbonyl)-propylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

EXAMPLE 4(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

a. 4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-ethyl acetate

Prepared analogously to Example 1k from4-(5-methyl-1,2,4-oxadiazol-3-yl)-aniline and ethyl bromoacetate inN-ethyl-diisopropylamine.

Yield: 78% of theory, R_(f) value: 0.60 (silica gel; ethylacetate/petroleum ether=1:1)

b.4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonylamino-ethylacetate

Prepared analogously to Example 1c from4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylamino-ethyl acetate anddi-tert.butyldicarbonate/N-ethyl-diisopropylamine in dioxane.

Yield: 63% of theory, R_(f) value: 0.48 (silica gel; ethylacetate/cyclohexane=1:2)

c.4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminoaceticacid

A solution of 3.5 g (9.7 mmol) of4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonylamino-ethylacetate in 10 ml of tetrahydrofuran and 4 ml of methanol is combinedwith 9.7 ml of 1N sodium hydroxide solution (9.7 mmol) and stirred for 3hours at room temperature. The reaction mixture is evaporated down tohalf its volume and mixed with water. The pH value is adjusted to 4-5 bythe addition of glacial acetic acid, the precipitate formed is filteredoff, washed with water and dried.

Yield: 2.8 g (87% of theory), R_(f) value: 0.5 (Reversed phase RP8; 5%saline solution/methanol=1:3)

d.(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminomethyl]-1-methyl-5-[2-tert.butyloxycarbonylamino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Prepared analogously to Example 1 g/h from(R)-2-(4-methylamino-3-amino-phenyl)-2-tert.butyloxycarbonylamino-1-pyrrolidino-propanone,4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminoaceticacid and carbonyldiimidazole in tetrahydrofuran and subsequently treatedwith glacial acetic acid.

Yield: 47% of theory, R_(f) value: 0.46 (silica gel; ethyl acetate)

e.(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Prepared analogously to Example 1i from(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl-N-tert.butyloxycarbonyl-aminomethyl]-1-methyl-5-[2-tert.butyloxycarbonyl-amino-1-(pyrrolidino-carbonyl)-ethyl]-benzimidazoleand 6N hydrochloric acid.

Yield: 91% of theory, R_(f) value: 0.44 (silica gel; methylenechloride/methanol/ammonia=9:0.9:0.1)

f.(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-cyanomethylamino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Prepared analogously to Example 1k from(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand bromoacetonitrile/potassium carbonate in acetone.

Yield: 72% of theory, R_(f) value: 0.54 (silica gel; ethylacetate/ethanol=9:1+1% ammonia) C₂₇H₃₀N₈O₂ (498.59) Mass spectrum:(M+H)⁺=499 (M−H)⁻=497 (M+Na)⁺=521

g.(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

1.1 g (2.2 mmol) of(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-cyanomethylamino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare suspended in 20 ml of toluene and 60 ml of dioxane and combined with2.2 g (6.6 mmol) of tributyl tin azide. The reaction mixture is heatedto 130° C. for 6 hours. After the solvent has been evaporated off, theresidue is triturated with petroleum ether, filtered, washed withpetroleum ether and dried. The crude product is purified on silica gel,eluting with methylene chloride/methanol 20:1 and 9:1. The uniformfractions are combined and concentrated by evaporation.

Yield: 0.7 g (59% of theory) R_(f) value: 0.33 (silica gel; methylenechloride:methanol=9:1) C₂₇H₃₁N₁₁O₂ (541.6) Mass spectrum: (M−H)⁻=540(M+Na)⁺=564

h.(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Prepared analogously to Example 1h from(R)-2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenylaminomethyl]-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand hydrogen/palladium (20% on activated charcoal) in ethanol/glacialacetic acid.

Yield: 63% of theory, R_(f) value: 0.35 (Reversed phase RP8; 5% salinesolution/methanol=4:3) C₂₅H₃₁N₁₁O (501.6) Mass spectrum: (M+H)⁺=502(M−H)⁻=500

EXAMPLE 52-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate

a. methyl 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate

35 ml of a 1.6 molar solution of n-butyllithium in hexane (61 mmol) areadded dropwise to a solution of 8.1 ml of diisopropylamine (85 mmol) in20 ml of tetrahydrofuran at −78° C. Then a solution of 10.0 g (50 mmol)of methyl 2-(4-chloro-phenyl)-propionate in 30 ml of tetrahydrofuran isadded dropwise at −78° C. Gaseous formaldehyde is piped into thereaction mixture at −20° C. for 30 minutes. After the addition of 5%citric acid and glacial acetic acid the mixture is extracted with ethylacetate. The organic phases are washed with 1N sulphuric acid, water,saturated sodium bicarbonate solution and saline solution and dried overmagnesium sulphate. The crude product is purified on silica gel, elutingwith cyclohexane/ethyl acetate (19:1; 9:1; 4:1; 1:1 and 0:1). Theuniform fractions are combined and concentrated by evaporation.

Yield: 9.7 g of yellow oil (84% of theory), R_(f) value: 0.25 (silicagel; petroleum ether/ethyl acetate=4:1)

b. 2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid

Prepared analogously to Example 8 from methyl2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionate and sodium hydroxidesolution in ethanol.

Yield: 83% of theory, R_(f) value: 0.55 (silica gel; ethylacetate/cyclohexane=2:1+1% glacial acetic acid)

c. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-nitroxy-propionic acid

Prepared analogously to Example 1a from2-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid and nitric acid.

Yield: 90% of theory, Melting point: 129-132° C. C₁₀H₉ClN₂O₇ (304.64)

d. 2-(4-chloro-3-nitro-phenyl)-2-methyl-3-hydroxy-propionic acid

Prepared analogously to Example 1i from2-(4-chloro-3-nitro-phenyl)-3-nitroxy-2-methyl-propionic acid and 6Nhydrochloric acid in dioxane.

Yield: 98% of theory, C₁₀H₁₀ClNO₅ (259.65) Mass spectrum: (M−H)⁻=258/60(Cl) (2M−H)⁻=517/9 (Cl₂)

e.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-propionicacid

Prepared analogously to Example 1e from2-(4-chloro-3-nitro-phenyl)-3-hydroxy-2-methyl-propionic acid andN-methyl-benzylamine.

Yield: 81% of theory, C₁₈H₂₀ClN₂O₅ (344.37) Mass spectrum: M⁺=344

f.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidin-1-yl-propan-1-one

Prepared analogously to Example 1e from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionicacid and pyrrolidine.

Yield: 96% of theory, C₂₂H₂₇N₃O₄ (397.48) Mass spectrum: M⁺=398(M+Na)⁺=420

g.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-ethoxycarbonylmethyloxy-1-pyrrolidino-propan-1-one

A solution of 8.0 g (20 mmol) of2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidino-propan-1-oneand 5 ml (48 mmol) of ethyl diazoacetate in 50 ml of methylene chlorideis mixed with 2.0 ml of boron trifluoride-diethylether complex (16 mmol)at room temperature and refluxed for 14 hours. After cooling, thereaction solution is stirred into ice water and the organic phase isseparated off. The aqueous phase is extracted three times with methylenechloride, the combined organic phases are washed with saline solution,dried over sodium sulphate and concentrated by evaporation. The residueis dissolved in ethyl acetate and purified on silica gel, extractinginitially with petroleum ether, then with petroleum ether/ethyl acetate(1:1). The uniform fractions are combined and concentrated byevaporation.

Yield: 2.5 g (26% of theory), R_(f) value: 0.6 (silica gel; ethylacetate) C₂₆H₃₃N₃O₆ (483.57) Mass spectrum: (M+H)⁺=484

h.2-(4-methylamino-3-amino-phenyl)-2-methyl-3-ethoxycarbonylmethyloxy-1-pyrrolidino-propan-1-one

Prepared analogously to Example 1f from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-ethoxymethyloxy-1-pyrrolidin-1-yl-propan-1-oneand hydrogen/palladium on activated charcoal.

Yield: 81% of theory, R_(f) value: 0.40 (silica gel; methylenechloride/ethanol=19:1)

i.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl-benzimidazole

Prepared analogously to Example 1g/h from2-(4-methylamino-3-amino-phenyl)-2-methyl-3-ethoxycarbonylmethyloxy-1-pyrrolidino-propan-1-one,4-cyano-phenylglycine/O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and subsequently treated with glacial acetic acid.

Yield: 77% of theory, R_(f) value: 0.40 (silica gel; methylenechloride/ethanol=19:1) C₂₈H₃₃N₅O₄ (503.61) Mass spectrum: (M+H)⁺=504(M+Na)⁺=526

k.2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-acetate

Prepared analogously to Example 11 from2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand hydrochloric acid/ammonium carbonate in ethanol.

Yield: 64% of theory, R_(f) value: 0.25 (silica gel; methylenechloride/ethanol=4:1+1% glacial acetic acid) C₂₈H₃₆N₆O₄×CH₃COOH(520.63/580.69) Mass spectrum: (M+H)⁺=521

EXAMPLE 62-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride

a.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-one

A solution of 1.2 g (3.0 mmol) of2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidino-propan-1-onein 20 ml of tetrahydrofuran is combined at room temperature with 1.3 mlof (9.3 mmol) of triethylamine. Then 0.27 ml (3.5 mmol) ofmethanesulphonylchloride are added dropwise at 2-5° C. After 2 hours atroom temperature the precipitate formed is suction filtered and thefiltrate is concentrated by evaporation. The crude product is reactedfurther without purification.

Yield: 1.4 g (98% of theory).

b.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-cyano-1-pyrrolidine-propan-1-one

A solution of 8.2 g (17 mmol) of2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-onein 125 ml of dimethylformamide is mixed with 1.8 g (27 mmol) ofpotassium cyanide and heated to 100° C. for 2 hours. After cooling, thereaction solution is stirred into ice water and extracted 3× with ethylacetate. The combined organic phases are washed with saline solution anddried over sodium sulphate. The crude product is dissolved in methylenechloride and purified on silica gel, eluting initially with methylenechloride, then with methylene chloride/ethanol (50:1 and 25:1). Theuniform fractions are combined and concentrated by evaporation.

Yield: 5.0 g (72% of theory) R_(f) value: 0.45 (silica gel; methylenechloride/ethanol=19:1) C₂₃H₂₆N₄O₃ (406.49) Mass spectrum: M⁺=406(M+Na)⁺=429

c.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one

Prepared analogously to Example 4g from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-cyano-1-pyrrolidino-propan-1-oneand tributyl tin azide.

Yield: 37% of theory, R_(f) value: 0.55 (silica gel; methylenechloride/ethanol=9:1) C₂₃H₂₇N₇O₃ (449.52) Mass spectrum: (M+Na)⁺=472(M−H)⁻=448

d.2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one

Prepared analogously to Example 1f from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-oneand hydrogen/palladium on activated charcoal.

Yield: 48% of theory, R_(f) value: 0.3 (silica gel; methylenechloride/ethanol=9:1) C₁₆H₂₃N₇O (329.41) Mass spectrum: (M+H)⁺=330(M−H)⁻=328

e.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Prepared analogously to Example 1g/h from2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(1H-tetrazol-5-yl)-1-pyrrolidino-propan-1-one,4-cyano-phenylglycine/O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and subsequently treating with glacial acetic acid.

Yield: 17% of theory, R_(f) value: 0.25 (silica gel; methylenechloride/ethanol=9:1) C₂₅H₂₇N₉O (469.55) Mass spectrum: (M−H)⁻=468

f.2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride

Prepared analogously to Example 11 from2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand hydrochloric acid/ammonium carbonate in ethanol.

Yield: 25% of theory, R_(f) value: 0.35 (Reversed phase RP8; 5% salinesolution/methanol=1:1) C₂₅H₃₀N₁₀O×HCl (486.58/523.05) Mass spectrum:(M+H)⁺=487

EXAMPLE 72-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-diacetate

a.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-azido-1-pyrrolidino-propan-1-one

Prepared analogously to Example 6b from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-methanesulphonyloxy-1-pyrrolidino-propan-1-oneand sodium azide in dimethylformamide.

Yield: 100% of theory, R_(f) value: 0.75 (silica gel; ethylacetate/petroleum ether=1:1) C₂₂H₂₆N₆O₃ (422.49) Mass spectrum: M⁺=422

b.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-amino-1-pyrrolidino-propan-1-one

A solution of 24.75 g (59 mmol) of2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-azido-1-pyrrolidino-propan-1-oneand 15.7 g (60 mmol) of triphenylphosphine in 250 ml of tetrahydrofuranand 1.8 ml of water is stirred for 60 hours at room temperature. Afterevaporation of the solvent the residue is purified over silica gel,eluting first with methylene chloride, then with methylenechloride/ethanol (50:1, 9:1, 8:2 and 7:3). The uniform fractions arecombined and concentrated by evaporation.

Yield: 21.7 g (93% of theory), R_(f) value: 0.25 (Reversed phase RP8; 5%saline solution/methanol=2:3) C₂₂H₂₈N₄O₃ (396.49) Mass spectrum:(M+H)⁺=397

c.2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-one

Prepared analogously to Example 1c from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-amino-1-pyrrolidino-propan-1-oneand di-tert.butyldicarbonate/N-ethyl-diisopropylamine in dioxane.

Yield: 98% of theory, R_(f) value: 0.55 (silica gel; methylenechloride/ethanol=19:1) C₂₇H₃₆N₅O₄ (496.61) Mass spectrum: M⁺=496(M+Na)⁺=519 (M−H)⁻=495

d.2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-one

Prepared analogously to Example 1f from2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-oneand hydrogen/palladium on activated charcoal.

Yield: 23% of theory, R_(f) value: 0.4 (silica gel; methylenechloride/ethanol=19:1) C₂₀H₃₂N₄O₃ (376.5) Mass spectrum: (M+Na)⁺=399(M−H)⁻=375

e.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(tert.butyloxycarbonylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Prepared analogously to Example 1g/h from2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(tert.butyloxycarbonylamino)-1-pyrrolidino-propan-1-one,4-cyano-phenylglycine/carbonyldiimidazole and subsequent treatment withglacial acetic acid.

Yield: 58% of theory, R_(f) value: 0.5 (aluminium oxide; methylenechloride/ethanol=19:1) C₂₉H₃₆N₆O₃ (516.65) Mass spectrum: M⁺=516(M+Na)⁺=539

f.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-aminomethyl-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Prepared analogously to Example 1i from2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(tert.butyloxycarbonylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand 6N hydrochloric acid in dioxane.

Yield: 82% of theory, R_(f) value: 0.25 (silica gel; methylenechloride/ethanol=9:1)

g.2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Prepared analogously to Example 1k from2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-aminomethyl-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand ethyl bromoacetate/potassium carbonate in acetone.

Yield: 25% of theory, R_(f) value: 0.6 (silica gel; methylenechloride/ethanol=9:1) C₂₈H₃₄N₆O₃ (502.62) Mass spectrum: (M+H)⁺=503(M+Na)⁺=525 (M−H)⁻=501

h.2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-diacetate

Prepared analogously to Example 1l from2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand hydrochloric acid/ammonium carbonate in ethanol.

Yield: 66% of theory, R_(f) value: 0.35 (silica gel; methylenechloride/ethanol=4:1+1% glacial acetic acid) C₂₈H₃₇N₇O₃×2 CH₃COOH(519.65/639.76) Mass spectrum: (M+H)⁺=520

The following compounds are obtained analogously to Example 7:

(1)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-(2-ethoxycarbonyl-ethyl)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

(2)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycarbonylmethylsulphonyl)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

(3)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-ethoxycarbonylmethylaminocarbonyl-N-methyl-aminomethyl)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-hydrochoride

Yield: 55% of theory, R_(f) value: 0.4 (Reversed phase RP8; 5% salinesolution/methanol=1:1) C₃₀H₃₈N₈O₄×HCl (574.36/610.81) Mass spectrum:(M+H)⁺=575 (M−H)⁻=573 (M+Cl)⁻=609/611 (Cl)

EXAMPLE 8

(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochloride(mixture of diastereomers)

A solution of 500 mg (0.84 mmol) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochloride(mixture of diastereomers) in 4 ml of water is mixed with 2.7 ml of 1Nsodium hydroxide solution and stirred for 45 minutes at roomtemperature. The pH value of the solution is adjusted to 3.5 by addingIN hydrochloric acid. The solution is concentrated by evaporation withthe addition of toluene and the residue is mixed with a little methanol.After the undissolved inorganic material has been filtered off, thefiltrate is concentrated by evaporation and triturated with ether. Thesolid formed is filtered off and dried.

Yield: 480 mg (100% of theory), R_(f) value: 0.5 (Reversed phase RP8; 5%saline solution/methanol=1:1) C₂₆H₃₃N₇O₃×2 HCl (491.6/564.51) Massspectrum: (M+H)⁺=492 (M+Na)⁺=514

The following compounds are obtained analogously to Example 8:

(1)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylaminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride

Yield: 70% of theory, R_(f) value: 0.45 (Reversed phase RP8; 5% salinesolution/methanol=1:1) C₂₆H₃₃N₇O₃×2 HCl (491.6/564.51) Mass spectrum:(M+H)⁺=492

(2)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride

Yield: 100% of theory, R_(f) value: 0.5 (Reversed phase RP8; 5% salinesolution/methanol=1:1) C₂₅H₂₉N₇O₃×2 HCl (475.55/548.46) Mass spectrum:(M+H)⁺=476 (M−H)⁻=474

(3)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

Yield: 67% of theory, R_(f) value: 0.46 (silica gel; 5% methylenechloride/methanol/conc. ammonia=4:0.9:0.1) C₃₂H₃₅N₇O₄ (581.67) Massspectrum: (M+H)⁺=582 (M−H)⁻=580 (M+Na)⁺=604

(4)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethyloxymethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride

Yield: 45% of theory, R_(f) value: 0.4 (Reversed phase RP8; 5% salinesolution/methanol=1:1) C₂₆H₃₂N₆O₄×HCl (492.58/529.03) Mass spectrum:(M+H)⁺=493 (M−H)⁻=491

(5)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-(2-carboxyethyl)-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

(6)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxymethylsulphonyl-N-methyl-aminomethyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole

(7)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(N-carboxymethyaminocarbonyl)-N-methyl-aminomethyl)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-hydrochloride

Yield: 15% of theory, R_(f) value: 0.5 (Reversed phase RP8; 5% salinesolution/methanol=1:1) C₂₈H₃₄N₈O₄×HCl (546.62/583.09) Mass spectrum:(M+H)⁺=547 (M−H)⁻=545 (M+C)⁻=581/583 (Cl)

EXAMPLE 9

Dry ampoule containing 75 mg of active substance per 10 ml

Composition

Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0ml

Preparation:

Active substance and mannitol are dissolved in water. After packagingthe solution is freeze-dried. To produce the solution ready for use, theproduct is dissolved in water for injections.

EXAMPLE 10

Dry ampoule containing 35 mg of active substance per 2 ml

Composition

Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0ml

Preparation

Active substance and mannitol are dissolved in water. After packaging,the solution is freeze-dried.

To produce the solution ready for use, the product is dissolved in waterfor injections.

EXAMPLE 11

Tablet containing 50 mg of active substance

Composition

(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate  2.0 mg 215.0mg 

Preparation

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side. Diameter of the tablets: 9 mm.

EXAMPLE 12

Tablet containing 350 mg of active substance

Preparation

(1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5) Magnesium stearate  4.0mg 600.0 mg

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side. Diameter of the tablets: 12 mm.

EXAMPLE 13

Capsules containing 50 mg of active substance

Composition

(1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powderedlactose 50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mg 

Preparation

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatin capsules in acapsule filling machine.

EXAMPLE 14

Capsules containing 350 mg of active substance

Composition

(1) Active substance 350.0 mg (2) Dried maize starch  46.0 mg (3)Powdered lactose  30.0 mg (4) Magnesium stearate  4.0 mg 430.0 mg

Preparation

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatin capsules in acapsule filling machine.

EXAMPLE 15

Suppositories containing 100 mg of active substance

1 suppository contains: Active substance 100.0 mg Polyethyleneglycol(M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mgPolyethylenesorbitan monostearate 840.0 mg 2,000.0 mg  

Method

The polyethyleneglycol is melted together with polyethylene sorbitanmonostearate. At 40° C. the ground active substance is homogeneouslydispersed in the melt. It is cooled to 38° C. and poured into slightlychilled suppository moulds.

What is claimed is:
 1. A compound of the formula

wherein R_(a) denotes a straight-chained C₁₋₃-alkyl group wherein thehydrogen atoms may be wholly or partially replaced by fluorine atoms andwhich is substituted in the 1 position by: (a) a pyrrolidinocarbonyl or2,5-dihydropyrrolocarbonyl group optionally substituted by a C₁₋₃-alkylgroup and (b) a moiety which is: (1) an ammo group which ismonosubstituted by a carboxy-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl ortetrazolyl-C₁₋₄-alkyl group, or (2) a C₁₋₃-alkyl group which isterminally substituted by: (a) anN-(carboxy-C₁₋₃-alkylaminocarbonyl)-amino group optionally substitutedby a C₁₋₃-alkyl group at one or both amino nitrogen atoms, (b)carboxy-C₁₋₃-alkoxy, (c) N-(carboxy-C₁₋₃-alkyl) -amino, (d)N—C₁₋₃-alkyl)-N-(carboxy-C₁₋₃-alkyl)-amino, (e)N-(carboxy-C₁₋₃-alkylsulphonyl)-amino, (f)N—(C₁₋₃-alkyl)-N-(carboxy-C₁₋₃-alkylsulphonyl)-amino or (g) atetrazolyl-C₁₋₃-alkyl group, R_(b) denotes a C₁₋₃-alkyl group and R_(c)denotes an amidino group, a cyano group or a 1,2,4-oxadiazol-3-yl groupsubstituted in the 5 position by a C₁₋₃-alkyl or phenyl group, while thephenyl substituent may be substituted by a fluorine, chlorine or bromineatom or by a C₁₋₃-alkyl group, wherein any carboxy group mentionedherein before may optionally be replaced by a group which can beconverted in vivo into a carboxy group, selected from a hydroxmethylgroup, a carboxy group esterified with an alcohol wherein the alcoholicmoiety is a C₁₋₆-alkanol, a phenyl-C₁₋₃-alkanol, a C₁₋₉-cycloalkanol,whilst a C₅₋₈-cycloalkanol may additionally be substituted by one or twoC₁₋₃-alkyl groups, a C₅₋₈-cycloalkanol, wherein a methylene group in the3 or 4 position is replaced by an oxygen atom or by an imino groupoptionally substituted by a C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl,phenyl-C₁₋₃-alkoxycarbonyl or C₂₋₆-alkanoyl group and the cycloalkanolmoiety may additionally be substituted by one or two C₁₋₃-alkyl groups,a C₄₋₇-cycloalkenol, a C₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, aC₃₋₅-alkynol or phenyl-C₃₋₅-alkynol, with the proviso that no bond tothe oxygen atom starts from a carbon atom which carries a double ortriple bond, a C₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol having atotal of 8 to 10 carbon atoms which may additionally be substituted inthe bicycloalkyl moiety by one or two C₁₋₃-alkyl groups, a 1,3dihydro-3-oxo-1-isobenzofuranol or an alcohol of formulaR_(d)—CO—O—(R_(e)CR_(f))—OH,  wherein R_(d) denotes a C₁₋₈-alkyl,C₅₋₇-cycloalkyl, phenyl or phenyl-C₁₋₃-alkyl groups R_(e) denotes ahydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or phenyl group and R_(f)denotes a hydrogen atom or a C₁₋₃-alkyl group, or wherein any carboxygroup mentioned herein before may optionally be replaced by a groupwhich is negatively charged under physiological conditions, selectedfrom the group consisting of a tetrazol-5-yl,phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl,C₁₋₆-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino,trifluoromethylsulphonylamino, C₁₋₆-alkylsulphonylaminocarbonyl,phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl andperfluoro-C₁₋₆-alkylsulphonylaminocarbonyl group, and wherein any aminoor imino group mentioned herein before may optionally be substituted bya group which can be cleaved in vivo, selected from the group consistingof a hydroxy group, a benzoyl group optionally mono- or disubstituted byfluorine, chlorine, bromine or iodine atoms or by C₁₋₃-alkyl orC₁₋₃-alkoxy groups, whilst the substituents may be identical ordifferent, a pyridinoyl group, a C₁₋₁₆-alkanoyl group, a3,3,3-trichloropropionyl or allyloxycarbonyl group, aC₁₋₁₆-alkoxycarbonyl or C₁₋₁₆-alkylcarbonyloxy group wherein hydrogenatoms may be wholly or partially replaced by fluorine or chlorine atoms,a phenyl-C₁₋₆-alkoxycarbonyl group, a 3-amino-propionyl group whereinthe amino group may be mono- or disubstituted by C₁₋₆-alkyl orC₃₋₇-cycloalkyl groups and the substituents may be identical ordifferent, a C₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl,R_(d)—CO—O—(R_(d)CR_(f))—O—CO, C₁₋₆-alkyl-CO—NH—(R_(g)CR_(h))—O—CO orC₁₋₆-alkyl-CO—O—(R_(g)CR_(h))—(R_(g)CR_(h))—O—CO group wherein R_(d) toR_(f) are as hereinbefore defined, R_(g) and R_(h) which may beidentical or different, denote hydrogen atoms or C₁₋₃-alkyl groups andwherein the saturated alkyl and alkoxy moieties which contain more than2 carbon atoms mentioned in the above definitions also include thebranched isomers thereof, or a tautomer or a salt thereof.
 2. A compoundof the formula I according to claim 1, wherein R_(a) denotes an ethylgroup which is substituted in the 1 position by a2,5-dihydropyrrolocarbonyl group optionally substituted by a methylgroup and by an amino group which is substituted by aC₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl group, by a carboxy-C₁₋₄alkyl,cyclohexyloxycarbonyl-C₁₋₄-alkyl or tetrazolyl-C₁₋₄-alkyl group, or by aC₁₋₃-alkyl group which is terminally substituted by anN-(carboxy-C₁₋₃alkylaminocarbonyl)-amino orN—(C₁₋₃alkoxycarbonyl-C₁₋₃-alkylaminocarbonyl)-amino group optionallysubstituted at one or both amino nitrogen atoms by a C₁₋₃-alkyl group,by a carboxy-C₁₋₃-alkoxy, C₁₃-alkoxycarbonyl-C₁₋₃alkoxy,N—(C₁₋₃-alkyl)-N-(carboxy-C₁₋₃-alkyl)-amino,N—(C₁₋₃-alkyl)-N—(C₁₋₃alkoxycarbonyl-C₁₋₃alkyl)-amino,N—(C₁₋₃-alkyl)-N-(carboxy-C₁₋₃alkylsulphonyl)-amino orN—(C₁₋₃-alkyl)-N—(C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylsulphonyl)-amino ortetrazolyl-C₁₋₃alkyl group, R_(b) denotes a methyl group and R_(c)denotes an amidino group optionally substituted by a benzoyl,methylbenzoyl or fluorobenzoyl group or R_(a) denotes an ethyl groupwhich is substituted in the 1 position by a pyrrolidinocarbonyl groupand by an amino group, whilst the amino group is substituted by anethoxycarbonylmethyl group, by a carboxymethyl, propyloxycarbonylmethyl,isopropyloxycarbonylmethyl, isobutyloxycarbonylmethyl,cyclohexyloxycarbonylmethyl, 3-(C₂₋₃-alkoxycarbonyl)-propyl ortetrazolylmethyl group, R_(b) denotes a methyl group and R_(c) denotesan amidino group substituted by a benzoyl, methylbenzoyl orfluorobenzoyl group or R_(a) denotes an ethyl group which is substitutedin the 1 position by a pyrrolidinocarbonyl group substituted in the 2position by a methyl group and by an amino group, whilst the amino groupis substituted by a carboxymethyl or ethoxycarbonylmethyl group, R_(b)denotes a methyl group and R_(c) denotes an amidino group or R_(a)denotes an ethyl group which is substituted in the 1 position by apyrrolidinocarbonyl group and by an amino group substituted by acarboxymethyl or C₃₋₄-alkoxycarbonylmethyl group or by a methyl group,whilst the methyl group is substituted by a carboxymethoxy,ethoxycarbonylmethoxy, ethoxycarbonylmethylamino,N-(2-carboxyethyl)-N-methyl-amino,N-[2-(C₁₋₃-alkoxycarbonyl)-ethyl]-N-methyl-amino,N-(carboxymethylaminocarbonyl)-N-methyl-amino,N-(C₁₋₃-alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino,N-(carboxymethylsulphonyl)-N-methyl-amino orN-(C₁₋₃alkoxycarbonylmethylsulphonyl)-N-methyl-amino group, R_(b)denotes a methyl group and R_(c) denotes an amidino group, or a tautomeror salt thereof.
 3. A compound selected from the group consisting of:(a)(R)-2-[4-[N-(4-trifluoromethyl-phenylcarbonyl)amidino]-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,(b)(R)-2-[4-(N-n-hexyloxycarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,(c)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-methoxy-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,(d)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-dimethylamino-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,(e)(R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(2-(2-methylphenyl)-ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand (f)2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(1H-tetrazol-5-yl-methyl)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,or a tautomer or physiologically acceptable salt thereof.
 4. Aphysiologically acceptable salt of a compound according to claim 1 or 2,wherein R_(c) denotes an amidino group.
 5. A pharmaceutical compositioncontaining a compound according to claim 1 or 2, wherein R_(c) denotesan amidino group, or a physiologically acceptable salt thereof, or acompound according to claim 3, and a pharmaceutically acceptablecarrier.
 6. A method for inhibiting the formation of thromboses or fortreating thromboses which method comprises administering to a host inneed of such treatment an antithrombotic amount of a compound accordingto claim 1 or 2, wherein R_(c) denotes an amidino group, or aphysiologically acceptable salt thereof, or a compound according toclaim 3.